Aryl substituted-hydroxy substituted cyclohexenecarboxylic acids and esters

ABSTRACT

Hydroxyacids and hydroxyesters of the formula:   WHEREIN R is hydrogen or lower alkyl, R&#39;&#39; is lower alkyl and Ar is substituted aryl, are intermediates in the preparation of 2lower alkyl-3-lower alkyl-4-aryl-cyclohexenecarboxylic acids and esters which are active agents for the suppression of animal reproduction.

United States Patent [1 1 {111 3,742,028 Karmas June 26, 1973 ARYL SUBSTITUTED-HYDROXY SUBSTITUTED CYCLOHEXENECARBOXYLIC ACIDS AND ESTERS Inventor: George Karmas, Bound Brook, NJ.

Assignee: Ortho Pharmaceutical Corporation,

Raritan, NJ.

Filed: Sept. 23, 1970 Appl. No.: 74,857

Related U.S. Application Data Division of Ser. No. 662,295, Augl 22, 1967.

US. Cl... 260/479 R, 260/332.2 A, 260/471 A, 260/471 R, 260/473 A, 260/481 R, 260/999 Int. Cl. C07c 65/14 Field of Search 260/479 R OTHER PUBLICATIONS Nathan et al., Jour. Amer. Chem. Soc., Vol. 78 (1956), pages 6,163-6,l66.

Primary Examiner-James A. Patten Attorney-Alexander T. Kardos, Ralph T. Lilare et al.

[57] ABSTRACT Hydroxyacids and hydroxyesters of the formula:

0 u c 0 on C A1 i l wherein R is hydrogen or lower alkyl, R is lower alkyl and Ar is substituted aryl, are intermediates in the preparation of 2-lower alkyl-3-lower alkyl-4-ary1- cyclohexenecarboxylic acids and esters which are active agents for the suppression of animal reproduction.

4 Claims, No Drawings 1 ARYL SUBSTITUTED-HYDROXY SUBSTITUTED CYCLOI-IEXENECARBOXYLIC ACIDS AND ESTERS This is a division of application Ser. No. 662,295 filed Aug. 22, 1967.

The compounds of the present invention are of the formula:

wherein R is hydrogen or lower alkyl of up to eight carbon atoms, R is lower alkyl of up to six carbon atoms and Ar is wherein R, is hydrogen, hydroxy, lower alkoxy of up to four carbon atoms, lower acyloxy of up to five carbon atoms or tetrahydropyranyle 2-oxy, R is hydrogen, hydroxy, lower alkyl of up to four carbon atoms, lower alkoxy of up to four carbon atoms, lower acyloxy of up to five carbon atoms, chlorine, tetrahydropyranyl-2- oxy or trifluoromethyl and R is hydrogen, hydroxy, lower alkyl of up to 4 carbon atoms, lower acyloxy of up to five carbon atoms, diethylaminoethoxy, thiomethyl, trifiuoromethyl, dimethylamino tetrahydropyranyl-tetrahydrophyranyl-2-oxy, and wherein at least 1 and not more than 2 of R R and R is hydrogen; 3,4- methylenedioxyphenyl, a-naphthyl or ,B-naphthyl.

The compounds of the present invention are prepared by the saponification of their corresponding lactones or by the reaction of an aryl Grignard reagent or an aryl lithium compound and a 2-lower alkyl-3-lower a1kyl-4-ketocyclohexanecarboxylic acid. The preparation of the lactones is disclosed in my copending application Ser. No. 662,282 filed contemporaneously herewith now abandoned. The utility of the 2-lower alkyl-3- lower alkyl-4-aryl-cyclohexene-carboxylic acids and esters prepared from the compounds of the present invention is fully described in my copending application Ser. No. 662,311 filed contemporaneously herewith.

The preparation of the compounds of the invention is illustrated by the following reaction schemes:

The compounds of the invention are used to prepare the final 2 lower alkyl-3-lower alkyl-4-aryl cylohexenecarboxylic acids and esters according to the following reaction scheme:

1 It R Typical lactone starting materials for the compounds of the present invention are the lactones of:

2-methyl-3-ethyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid,

2,3-dimethyl-4-hydroxy-4-( m-anisyl)cyclohexanecarboxylic acid,

2,3-diethyl-4-hydroxy-4-( m-anisyl)cyclohexanecar- I boxylic acid,

2-methyl-3-propyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid,

2-propyl-3-butyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid,

2,3-dimethyl-4-hydroxy-4-( mtetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid,

2,3-diethyl-4-hydroxy-4-(mtetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid,

2-ethyl-3-butyl-4-hydroxy4-( 3 ,4-

methylenedioxyphenyl)cyclohexanecarboxylic acid,

2,3-diethyl-4-hydroxy-4-(ptrifluoromethylphenyl)cyclohexanecarboxylic acid,

2,3-dibutyl-4-hydroxy-4-(mtrifluoromethylphenyl)cyclohexanecarboxylic acid,

2-methyl-3-propyl-4-hydroxy-4-(o-methoxy-pacetoxyphenyl)cyclohexanecarboxylic acid,

2-methyl-3-butyl-4-hydroxy-4(o,p-

diacetoxyphenyl)cyclohexanecarboxylic acid,

The following examples illustrate the preparation of the compounds of the invention.

EXAMPLE I 2-Methyl-3-ethyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid A mixture of 10.0 g. of the lactone of 2-methyl-3- ethyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid, 10.0 g. of sodium hydroxide, ml. of methanol and 100 ml. of water is stirred and refluxed for two hours and is then diluted with 250 ml. of water and evaporated to remove the methanol. The solution is acidified with dilute hydrochloric acid, and is extracted with ether. The ether solution is rapidly washed with water, dried over anhydrous magnesium sulfate and filt'ered. The residue is recrystallized from ether to afford 2-methyl 3-ethyl-4-hydroxy-4--(m-anisyl)cyclohexanecarboxylic acid; m.p. 203-204C.

umax: 2.83, 5.87 and 5.94 (split), 7.78, 8.03, 10.23,

12.80, 14.27 p. (KBr) NMR (Pyn): 0.63, 0.75, 0.87; 1.46, 1.57; 2.96

Following the procedure of Example I, but starting with the appropriate lactone, there are prepared:

M.P., Example Compound formed 0. UV. max. (KBr) 11 2-methy13-ethy1-4- 187-188 2.82, 5.87 and 5.97

. hydroxy-4-(o-anisy0- (split), 7.74, 8.10,

cyrgohexanecarboxylic 0.67, 13.20 1. aci

III 2-methy1-3-et-hyl-i- 189-190 2.83, 5.90, 7.09, 10.37,

hydroxy-i-(p-thid 11.00, 12.29,. anisy1)-cyclohexanecarboxylic acid.

IV 2-methyl-3'ethyl-4 201-202 2.82, 5.90, 8.10, 10.32,

hydroxy-4-(p-to1yD- 12.27, 14.10,. cycohexauecarboxyllc aci V 2-methyl-3-ethyl-4- 154-155 2.82, .89, 8.01, 8.40,

hydrxy-4-(m-toly0- 0. 12.78, 62 cycohexanecarboxylic ac:

VI 2-methyl-3-ethyl-4- 200-201 2.83, 5.87 and 5.98

hydr0xy-4-(p-trifiu0ro- (split), 7.50, 8.92, 9.30, methylphenybcyclu- 11.81, 1202 hexanecarboxylie acid.

VII 2-metl1yl-3-ethy1-4- 160-170 2.85, 5.83 and 5.87

hydroxy-4-(m-tri- (split), 7.50, 8.60, lluoromethylphenyD- 8.02, 12.48, 14.22, cyclohcxanecarboxylic 14.49;. acid.

VIII 2-methy1-3-ethyl-4- 106-197 2.82, 5.86 and 5.94

hydroxy-4-(BA- (split), 8.00, 9.00, methylcnedioxy- 10.63, 12.35 phcnyncyclohexanecarhoxylic acid.

IX 2-methyl-3-ethyl-4- 177-178 2.82, 5.87 and 5.05

hydroxy-4-(a- (split), 7.70, 10.13, naphthyD-cyclohex- 11.60, 12.47, 12.89 1. anecarboxylic acid.

X 2-methy1-3-cthyl-4- 216-217 2.85, 5.90, 8.00, 8.58,

hydroxb-4-(B- 11.67, 12.20, 13.33 4. naphthy1)cyc1ohexanecarboxylic acid.

XI 2-methyl-3-ethyl-4- 164-166 2.83, 5.88, 8.02, 9.62, hydroxy-i-(a- 10.10, 11.79, 14.15, thienyl)-cyc1ohex- 14.33 anecarboxylic acid.

XII 2-methy1-3-cthy1-4- 142-143 2.88, 5.84, 8.23, 10.14, hydroxy-4-benzyl- 11.51, 13.03, 14.15;.1. cypohexanecarboxylic aci XIII 2-methy1-3-propy14-(p- 196-197 2.84, 5.90, 7. ,9.57,

anisyDcyclohexane- 11.90, .35 1.

earboxylic acid.

EXAMPLE XIV 2-Methyl-3-ethy1-4-hydroxy-4-(mtetrahydropyranyloxy-phenyl)cyclohexanecarboxylic acid A mixture of 10.0 g. of the lactone of 2-methyl-3- ethy1-4-hydroxy-4-(m-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid, 10.0 g. of sodium hydroxide, 100 ml. of methanol and 100 ml. of water is stirred and refluxed for two hours. It is then diluted with 250 ml. of water and evaporated to remove methanol. The insoluble oily material is removed by extraction with ether and is discarded. 200 ml. of methylene chloride is added to the solution and the mixture is stirred and is maintained at 05C. while making the mixture barely acidic with cold dilute hydrochloric acid. The methylene chloride phase is separated, washed twice with brine, dried over anhydrous magnesium sulfate and evaporated to a residue. The residue is recrystallized from ether to afford 2-methy1-3-ethyl-4-hydroxy-4-( mtetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid, m.p. 149151C.

umax: 2.83, 5.88, 8.02, 8.98, 9.61, 10.34, 10.92 p.

(KBr) NMR (pyr.): 0.62, 0.73, 0.85; 1.46, 1.58; 2.95

Following the procedure of Example XIV, there are prepared:

EXAMPLE XV Z-Methyl-3-ethy1-4-hydroxy-4-(otetrahydropyranyloxyphenyl )cyclohexanecar boxylic acid; m.p. 164-166C.

umax: 2.88, 5.87, 0.13, 10.24, 10.85, 11.52, 13.28 p.

(KBr) NMR (pyr.): 0.67, 0.79, 0.90; 1.47, 1.58; 2.97

EXAMPLE XVI Z-Methyl-3-ethyl-4-hydroxy-4-(o-methoxy-ptetrahydro-pyranyloxyphenyl)cyclohexanecarboxylic acid, m.p. 118130C.

,umax: 2.86, 5.87, 8.31, 9.62, 10.10, 11.04, 11.92 ,u.

(KBr) NMR (pyr.): 0.65, 0.76, 0.88; 1.46, 1.57; 2.93 NMR (CDC1 0.67, 0.78, 0.89; 1.02, 1.13; 1.82,

EXAMPLE XVII Z-Methyl-3-ethyl-4-hydroxy-(o,p-bistetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid, m.p. 108C.

,umaxi 2.88, 5.87, 7.99, 9.61, 9.97, 10.38, 10.95,

1 1.85 p (KBr) NMR (pyr): 0.73, 0.85, 0.96; 1.52, 1.63; 2.98

Calcd. for C d-1 0 C, 67.51; H, 8.28

Found C, 67.00;11, 8.33

EXAMPLE XVIII 2-Methyl-3-ethyl-4-hydroxy-4-(m-hydroxyphenyl)- cyclohexanecarboxylic acid A suspension of 10.0 g. of 2-methyl-3-ethyl-4- hydroxy-4-(m-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XIV) in 260 m1. of methanol containing 35 m1. of water and 1.5 ml. of 12N hydrochloric acid is stirred at 25C. for forth minutes. To the resulting clear solution is added 260 m1. of water and 5 ml. of pyridine and the solution is evaporated to remove methanol while precipitating the phenolic hydroxy acid. The mixture is acidified with dilute hydrochloric acid and the product is extracted with ether. The ether solution is washed twice with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is recrystallized from ether-methylene chloride to afford 2-methyl3- ethy1-4-hydroxy-4-(m-hydroxyphenyl)cyclohexanecarboxylic acid, m.p. 21 1213C.

umax: 2.96, 3.15, 5.78, 7.50, 9.60. 1026,1268, 13.-

31, 14.23 p. (KBr) NMR (pyr.): 0.63, 0.74, 0.85; 1.45, 1.57; 2.92

' EXAMPLE XIX 2-Methyl-3-ethyl-4-hydroxy-4-(o-hydroxyphenyl)- cyclohexanecarboxylic acid Following the procedure of Example XVIII, but starting with Z-methyl-3-ethyl4-hydroxy-4-(otetrahydropyranyloxyphenyl )-cyclohexanecarboxylic acid (as prepared in Example XV), ther is afforded 2- methyl-3-ethy1-4-hydroxy-4-(o-hydroxyphenyl)cyclohexanecarboxylic acid, m.p. -191C.

,umax: 2.82, 3.04, 5.90, 8.06, 10.40, 10.69, 10.92,

13.23 [.L (KBr) NMR (pyr.): 0.67, 0.78, 0.89; 1.42, 1.53; 2.96

EXAMPLE XX 2-Methy1-3-ethyl-4-hydroxy-4-(o,p-

acid, m.p.

EXAMPLE XXI 2-Methyl-3-ethyl-4-hydroxy-4-(o-methoxy-phydroxyphenyl-cyclohexanecarboxylic acid Following the procedure of Example XVIII, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(o-methoxy-ptetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XVI), there is afforded 2-methyl-3-ethy1-4-hydroxy-4-(o-methoxy-phydroxyphenyl)cyclohexanecarboxylic acid, 128-131C.

umax: 2.95, 5.88, 8.31, 9.65, 10.33, 11.97 p. (KBr) NMR (pyr.): 0.67, 0.78, 0.90; 1.46, 1.57; 2.94

EXAMPLE XXII 2-Methy1-3-ethyl-4-hydroxy-4-( m-acetoxyphenyl)cyclohexanecarboxylic acid To a solution of 2.0 g. of 2-methyl-3-ethyl-4-hydroxy- 4-(m-hydroxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XVIII), in 25 ml. of pyridine is added with stirring 3 ml. of acetic anhydride. The solution is maintained at 25C. for twenty hours and is then hydrolyzed with ice and water. The oily products are extracted with ether. The ether solution is washed with cold dilute hydrochloric acid to remove pyridineand is then extracted with three cold portions of 7 percent aqueous potassium carbonate with each successive carbonate wash being immediately acidified with dilute hydrochloric acid. A tacky precipitate from the carbonate solutions is extracted with ether and the combined ether solution is dried and evaporated at 25C. The residue is recrystallized from ether to afford 2- methyl-3-ethyl-4-hydroxy-4 (m-acetoxyphenyl)cyclohexanecarboxylic acid, m.p. 172l73C.

umax: 2.83, 5.68, 8.30, 9.63, 10.71, 12.73 p. (KBr) NMR'(pyr.): 0.61, 0.71, 0.82; 1.44, 1.55; 2.94

EXAMPLE xxm 2-Methyl-3-ethyl-4-hydroxy-4-( o-acetoxyphenyl cyclohexanecarboxylic acid Following the procedure of Example XXII, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(ohydroxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XIX), there is afforded 2-methyl-3 ethyl-4-hydroxy-4-(oacetoxyphenyl)cyclohexanecarboxylic acid, m.p. 132-133C.

umax: 2.82, 5.72, 5.89, 8.20, 8.48, 13.09 p. (KBr) NMR (pyr.): 0.68, 0.80, 0.91; 1.43, 1.55; 2.96

EXAMPLE XXIV 2-Methyl-3-ethyl-4-hydroxy-4-(o,pdiacetoxyphenyl)cyclohexanecarboxylic acid Following the procedure of Example XII, but starting with 2-methyl-3-ethyl-4-hydr0xy-4-(o,pdihydroxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XX), there is afforded 2-methyl-3- ethy1-4-hydroxy-4-(o,p-diacetoxyphenyl)cyclohexanecarboxylic acid, m.p. ll0-112C.

umax: 2.85, 5.68, 8.10-8.40, 9.80, 10.87 u (KBr) NMR(CDC1, 0.64, 0.75, 0.86; 0.99, 1.10; 1.89,

The o-acetoxyphenyl-hydroxy acids prepared according to Examples XXIII and XXIV are unstable and begin to decompose after a few days at 25C. They are fully decomposed within two to three weeks at 25C. The decomposition follows the route:

Compounds I and II are mixtures of the A and A isomers.

EXAMPLE XXV 2-Methyl-3-ethyl-4-hydroxy-4-(m-chlorophenyl)- cyclohexanecarboxylic acid The Grignard reagent from 0.32 mole of mchlorobromobenzene, prepared in a mixture of ether and tetrahydrofuran, is stirred at -40 and to it is added 0.1 mole of 2-methyl-3-ethyl-4-ketocyclohexanecarboxylic acid in 40 ml. of tetrahydrofuran. This reaction mixture is stirredvigorously and heated at the reflux temperature for two hours and then it is cooled in ice and hydrolyzed with 400 ml. of saturated aqueous ammonium acetate. After filtration to remove magnesium, the layers are separated and the organic phase is dried and evaporated to a tacky, semi-crystalline residue. Recrystallization from ether or nitromethane affords 9.0 g. of 2-methyl-3-ethyl-4-hydroxy-4-(m-chlorophenyl)- cyclohexanecarboxylic acid, m.p. l66l69C.

umax: 2.83, 5.89, 8.01, 12.77, 13.79 p. (KBr) NMR (Pyn): 0.59, 0.70, 0.80; 1.40, 1.52; 2.92

The alkyl esters of the compounds of the invention are prepared by treatment of metal salts of the hydroxyacids with an appropriate dialkyl sulfate.

EXAMPLE XXVI Methyl-2-methyl-3-ethyl-4-hydroxy-4-phenylcyclohexanecarboxylate A solution of 4.0 g. of 2-methyl-3-ethyl-4-hydroxy-4- phenylcyclohexanecarboxylic acid and 1.5 g. of sodium hydroxide in 40 ml. of methanol and 150 ml. of dimethylformamide is evaporated under vacuum to a volume of ml. The resulting suspension is stirred and cooled to 15C. 3.5 ml. of dimethyl sulfate is added and the mixture is stirred at 25C. for thirty minutes and is then evaporated under vacuum to remove most of the dimethylformamide. The residue of about 15-20 ml. is shaken with ether and water, and the ether solution is washed with cold percent sodium hydroxide, followed by four portions of water. The ether solution is dried and evaporated to a residue. The residue is recrystallized from hexane to afford methyl 2-methyl-3- ethyl-4-hydroxy-4-phenylcyclohexanecarboxylate, m.p. ll2l 13C.

,umax: 2.87, 5.79, 8.21, 8.55, 13.29, 14.30 p. (KBr) Calcd for C H O C, 73.88; H, 8.75

Found C, 74.00; H, 8.76

EXAMPLE XXVII Methyl 2-methyl-3-ethyl-4-hydroxy-4-(ptrifluoromethylphenyl)cyclohexanecarboxylate Following the procedure of Example XXVI, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(ptrifluoromethylphenyl )cyclohexanecarboxylic acid, there is afforded methyl 2-methyl-3-ethyl-4-hydroxy-4- (p-trifluoromethylphenyl)cyclohexanecarboxylate, m.p. 112-113c.

tmax: 2.89, 5.88, 7.49, 7.82, 8.61, 8.90, 9.29, 9.84, 11.8], 12.04 p. (KBr) Calcd. for C H O F C, 62.79; H, 6.73

Found C, 63.07; H, 6.73

EXAMPLE XXVlll clohexanecarboxylate,

ethyl 2-ethyl-3-methyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

ethyl 2,3-dimethyl-4-hydroxy-4-benzylcyclohex anecarboxylate,

ethyl 2,3-diethyl-4-hydroxy-4-benzycyclohexanccarboxylate,

butyl 2-methyl-3-ethyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

butyl 2-ethyl-3-butyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

butyl 2-methyl-3-ethyl-4-hydroxy-4-(m-tolyl)cyclohexanecarboxylate. and

butyl Z-methyl-3-propyl-4-hydroxy-4-(m-toly1)cyclohexanecarboxylate.

What is claimed is:

1. A compound of the formula:

wherein R is selected from the group consisting of hy drogen and lower alkyl of up to eight carbon atoms, R is selected from the group consisting of lower alkyl of up to siX carbon atoms and Ar is selected from the group consisting of l ig l h 2. 2-Methyl-3-ethyl-4-hydroxy-4-( macetoxyphenyl)-cyclohexanecarboxylic acid according to claim 1.

3. 2-Methyl-3-ethyl-4-hydroxy-4-(o-acetoxyphenyl)- cyclohexanecarboxylic acid according to claim 1.

4. 2-Methyi-3-ethyl-4-hydroxy-4-(o,pdiacetoxyphenyl)-cyclohexanecarboxylic acid according to claim 1.

PC4050 UNITED STATES PATENT OFFICE 6 CERTIFICATE OF CORRECTION Patent No. 3,7"EUO28 Dated June J26, 973- Inventor(s) George Karmas Q It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In Column 1, line 32, "dimethylamino tetrahydropyranyl" should read "dimethylamino or tetrahydropyranyl" In Column 1, line 33, "delete second occurrence of tetrahydrophyranyl" In Column 3, lin3 l2, "12.78, .62m" should read----- 12.78, 1362m In Column 3, line 15, "2.85 5.83 and 5, 87" Q should read 5 5. 3 and 5.97"

In Column l, line 1, "0J3" should. read "8.13" In Column t, line 58, "they" should. read "there" In Column 5, line 66, "x11" should read. "XXll" In Column 6, 1in '7, "(CDClc8 )""should read "(CDCl In Column 8, Claim L' line '35, "claim 1 should continue wherein R1 R2 and R3 are hydrogen or lower alkoxy of up to 5 carbon atoms and wherein at least 1 and not more than 2 of R1, R2 and R3 is hydrogen Signed and sealed this 24th day of Se'iotember 1974.

(SEAL) Attest:

MCCOY M. GIBSON JR". r c. MARSH LL DANN V Attesting Officer Commissioner of Patents 

2. 2-Methyl-3-ethyl-4-hydroxy-4-(m-acetoxyphenyl)-cyclohexanecarboxylic acid according to claim
 1. 3. 2-Methyl-3-ethyl-4-hydroxy-4-(o-acetoxyphenyl)-cyclohexanecarboxylic acid according to claim
 1. 4. 2-Methyl-3-ethyl-4-hydroxy-4-(o,p-diacetoxyphenyl)-cyclohexanecarboxylic acid according to claim
 1. 